Parkinson's disease (PD) is one of the more common and serious neurodegenerative diseases characterized by degeneration of dopaminergic neurons in the brain, resulting in debilitating motor deficits such as tremor, rigidity, and akinesia, which have a severe impact on the patient as well as society. Dopamine replacement therapy with Levodopa (L-Dopa) is currently the standard pharmacotherapy for PD, but unfortunately, continued therapy with L-Dopa inevitably leads to serious motor fluctuations termed as L-Dopa induced dyskinesia (LID). LID can occur as early as 2-3 years after L-Dopa therapy and in as many as 80% of patients after 5 years of L-Dopa treatment. There are very limited treatment options for the prevention of LID or reduction of LID once established. Because of the lack of adequate treatment for LID, there is a significant decline in the quality of life of PD patients on L-Dopa therapy and a huge economic burden to the patient and to society due to the severity of the debilitating motor effects of LID. New pharmacotherapeutic approaches are urgently needed to treat LID and if possible, to prevent the occurrence of LID while treating Parkinson's symptoms. These side effects of dopamine replacement therapies have necessitated the investigation of nondopaminergic approaches for treatment of PD, that can reduce the occurrence of LID, or replace L-Dopa and other dopaminergic treatments for treating PD symptoms. Several non-dopaminergic approaches are being evaluated in clinical trials (5HT1A agonists, alpha adrenergic antagonists) and in preclinical studies (glutamate antagonists). However, several of these clinical-stage drugs have shown significant off-target effects and 'worsening'of PD symptoms, and have been unable to improve parkinsonism or dyskinesia scores. New targets and approaches are therefore needed to improve the long-term therapy of PD. This application proposes to investigate a new target and a novel therapeutic profile for the treatment of PD symptoms and importantly, for LID. We propose to investigate the nociceptin receptor NOP as a target for PD treatment and treatment of LID, and propose to develop NOP receptor ligands of desired profiles that are effective in reducing motor deficits associated with PD, as well as reducing or preventing symptoms of LID. The endogenous ligand for the NOP receptor, nociceptin/orphanin FQ (N/OFQ) has been shown to be upregulated in dopamine depletion states and contributes to PD symptoms. We propose to develop novel NOP receptor ligands possessing the desired receptor activity, and to investigate the proof of concept that these ligands afford protection against parkinsonian disabilities in hemilesioned rat models of PD and LID. The Aims of this proposal are to discover optimized novel potent NOP ligands using iterative medicinal chemistry;in vitro characterization in receptor binding and functional assays;early in vivo PK assessments and in vivo evaluation in animal models of PD and LID after acute administration. Our studies will provide critical validation of this novel therapeutic approach for PD and LID therapy, and also provide potentially novel drug candidates that can be further developed. Our translational approach to validate this novel target and novel drug profiles for PD treatment, in this short proof-of-concept study, has the potential to have a significant impact in an area of high unmet need and tremendous economic burden. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is one of the more common and serious neurodegenerative diseases and occurs in 2% of the population over 60. Its main therapy, L-Dopa, is associated with severe and worsening symptoms that inevitably occur after continued therapy, but for which there are very limited treatment options and no prevention therapies available. It is estimated that a PD patient spends about $11,000 more per year in medical costs than the average patient without PD. The annual cost burden of PD is estimated at $35 billion, in combined medical and drug costs, patient care and indirect costs of loss of productivity. None of the currently investigated approaches appear to have much clinical success;therefore there is significant room for exploring new approaches. Our proposal investigates a new, relatively unexplored target for PD therapy and L-Dopa induced dyskinesias, and proposes to develop novel drug candidates against this target, to validate this target as being suitable for developing much-needed pharmacotherapies against PD and dyskinesias. Successful completion of our studies has the potential to have a significant impact on the outcome of PD treatment.